Neural stem cells possess self-renewal and multilineage neural differentiation capacities and may promote functional recovery after injury through cell replacement, remyelination, neurotrophic support, and neural circuit reconstruction. As neural stem/progenitor cells and iPSC-derived cells advance into clinical studies, cell transplantation is becoming an important direction in neural regeneration research.

Keywords: neural stem cells; neural progenitor cells; neural injury; spinal cord injury; stroke; neural regeneration; remyelination; neural circuitry

1 Barriers to Neural Repair After Injury

1.1 Neuronal Loss and Axonal Disruption

Injury to the central nervous system can cause neuronal death and axonal disruption, resulting in loss of continuity within neural pathways responsible for sensory, motor, or cognitive functions. Mature central nervous system neurons have limited regenerative capacity. Even when some neurons survive, their axons may be unable to cross the lesion and reconnect with appropriate downstream targets.

1.2 Demyelination and Neural Circuit Disruption

Damage to oligodendrocytes can cause axonal demyelination, reducing action-potential conduction velocity or leading to conduction block. Severe injury may also destroy local interneurons and long-range projection fibers, resulting in functional impairment involving neural cell loss, abnormal axonal conduction, and interruption of neural network connectivity.

1.3 Inflammation and the Regeneration-Inhibitory Microenvironment

Following injury, microglia, infiltrating immune cells, and reactive astrocytes rapidly alter the local microenvironment. Persistent inflammation, glial scarring, extracellular matrix remodeling, and myelin-associated inhibitory signals such as Nogo can restrict axonal extension. Ischemia, oxidative stress, and insufficient neurotrophic support may also reduce the survival of endogenous neural cells and transplanted cells.

2 Fundamentals of Neural Stem Cell Transplantation

2.1 Basic Characteristics of Neural Stem Cells

Neural stem cells (NSCs) possess self-renewal capacity and can generate neurons, astrocytes, and oligodendrocytes. Neural progenitor cells (NPCs) generally have more restricted proliferative and differentiation potential. Transplantation studies commonly use neural stem/progenitor cells at different stages of differentiation to balance expansion capacity, lineage controllability, and transplantation safety.

2.2 Major Sources of Neural Stem Cells

(1) Neural Tissue-Derived NSCs/NPCs

Cell populations with neural stem/progenitor characteristics can be isolated from fetal or other neural tissues. These cells have relatively well-defined neural lineage identities and have been used in several early clinical studies. Further development, however, is limited by tissue availability, large-scale expansion, and batch-to-batch consistency.

(2) Embryonic Stem Cell-Derived Neural Stem/Progenitor Cells

Embryonic stem cells (ESCs) possess strong self-renewal and pluripotent differentiation capacities and can be directionally induced to form neural stem/progenitor cells and specific neural lineages. Residual undifferentiated pluripotent stem cells must be controlled before transplantation to reduce the risks of abnormal proliferation and tumor formation.

(3) iPSC-Derived Neural Stem/Progenitor Cells

Induced pluripotent stem cells (iPSCs) can be expanded in vitro and directionally differentiated into NSCs/NPCs, providing a platform for standardizing cell sources, controlling regional identity, and generating specific neural lineages. iPSC-derived neural stem/progenitor cells have entered human studies for spinal cord injury.

2.3 Transplantation Timing and Injury Stage

The acute phase of injury is generally characterized by pronounced inflammation, ischemia, edema, and secondary cell death, which are unfavorable for transplanted-cell survival. During the subacute phase, acute inflammation has partially subsided, while a stable scar has not yet fully formed, making this period an important transplantation window in several spinal cord injury studies. Chronic injury involves more stable tissue defects, glial scarring, and long-term circuit disruption, imposing greater demands on graft survival, axonal extension, and neural network integration.

3 Major Mechanisms of Neural Repair Promoted by Neural Stem Cells

3.1 Cell Replacement and Neural Circuit Reconstruction

Transplanted NSCs/NPCs can differentiate into neurons. After forming axons and dendrites, graft-derived neurons may establish synaptic connections with host neurons and form new relay networks within the lesion. In spinal cord injury models, host axons can enter the graft and connect with graft-derived neurons, which may subsequently extend axons toward regions distal to the lesion, providing a structural basis for restoring neural information transmission across the injured area.

3.2 Remyelination and Axonal Support

NSCs/NPCs can generate oligodendrocyte-lineage cells that form new myelin sheaths around demyelinated axons, improve action-potential conduction, and maintain axonal stability. Grafts may also support surviving axons within the injured area and improve the survival and structural integrity of local nerve fibers.

3.3 Neurotrophic and Paracrine Regulation

Transplanted cells can release neurotrophic or growth-associated factors such as BDNF, GDNF, VEGF, and HGF, thereby regulating neuronal survival, axonal growth, angiogenesis, and synaptic plasticity. Functional improvement in some injury models does not depend entirely on the long-term replacement of host neurons by transplanted cells; neuroprotection and endogenous repair mediated by paracrine signaling also contribute to tissue recovery.

3.4 Regulation of Inflammation and the Injury Microenvironment

NSCs/NPCs can influence the response states of microglia, macrophages, and astrocytes and regulate inflammatory mediators, oxidative stress, and the extracellular matrix environment. Attenuation of secondary tissue injury may improve the preservation of neurons, axons, and oligodendrocytes at the lesion margins, providing a tissue basis for subsequent neural network remodeling.

4 Major Research Directions in Neural Stem Cell Transplantation

4.1 Spinal Cord Injury

Spinal cord injury involves neuronal and oligodendrocyte loss, axonal disruption, demyelination, and a regeneration-inhibitory microenvironment. Transplanted cells may contribute to motor and sensory circuit repair by forming neuronal relays, replenishing oligodendrocytes, promoting host axonal growth, and releasing neurotrophic factors. Spinal cord injury is currently one of the most active areas of clinical translation for neural stem cell transplantation.

4.2 Ischemic Stroke

Cerebral ischemia can cause local neuronal death, neural network disruption, vascular injury, and persistent inflammation. Neural stem cell transplantation research in ischemic stroke has primarily focused on neural cell replacement, neurotrophic factor release, angiogenesis, and enhancement of host neural plasticity. Human neural stem cell products such as CTX0E03 have entered clinical studies in patients with stroke.

4.3 Traumatic Brain Injury

Traumatic brain injury (TBI) can cause neuronal death, diffuse axonal injury, blood-brain barrier disruption, and persistent neuroinflammation. Research on neural stem cells in TBI remains primarily at the preclinical stage and addresses transplanted-cell survival, neuroprotection, neurogenesis, axonal repair, and regulation of neuroinflammation.

5 Key Factors Affecting Neural Stem Cell Transplantation

5.1 Cell Source and Differentiation State

NSCs/NPCs from different sources vary in expansion capacity, regional identity, and lineage differentiation tendency. Highly immature cells possess stronger proliferative capacity but may carry a greater risk of abnormal proliferation, whereas extensively differentiated cells may show reduced survival and adaptability after transplantation. The proportions of neurons, astrocytes, and oligodendrocytes generated by the graft can also influence its eventual function.

5.2 Injury Stage and Local Microenvironment

Transplanted cells enter an injured tissue environment that continues to evolve. Acute inflammation, ischemia, and oxidative stress can reduce graft survival, whereas chronic glial scarring and axonal growth-inhibitory signals can restrict neurite extension and network integration. Spinal cord injury, stroke, and TBI follow different pathological courses, and their optimal transplantation windows may therefore differ.

5.3 Graft Survival and Functional Integration

Long-term cell survival is only the foundation of neural repair. Effective functional reconstruction also requires appropriate lineage differentiation, neurite extension, myelin formation, and synaptic integration, as well as the ability of graft-derived cells to receive host neural inputs and generate appropriately directed functional outputs.

5.4 Safety and Quality Control

Products derived from pluripotent stem cells require stringent control of residual undifferentiated cells, abnormal proliferation, and tumor-formation risks. Cell identity, genomic stability, differentiation potential, and batch-to-batch consistency must also be evaluated. Allogeneic transplantation additionally involves host immune responses and immunosuppression management. Long-term follow-up should continuously monitor abnormal tissue formation, graft overgrowth, and neurological adverse events.

6 Research Progress in Neural Stem Cell Transplantation

6.1 NSI-566

(1) Transplantation for Chronic Spinal Cord Injury

NSI-566 is a neural stem cell line derived from human spinal cord tissue. An early phase I study evaluated the safety and feasibility of transplantation in patients with chronic thoracic spinal cord injury. Cell transplantation was generally tolerated, and no clear graft-related serious safety signals were identified.

(2) Long-Term Follow-Up

Long-term observation identified changes in neurophysiological, motor, or sensory parameters in some patients, while no graft-related tumor formation was observed. Established tissue defects and neural circuit disruption in chronic spinal cord injury nevertheless continued to limit substantial functional recovery.

6.2 HuCNS-SC

(1) Study in Chronic Cervical Spinal Cord Injury

HuCNS-SC is a human neural stem cell product that was evaluated in a randomized proof-of-concept study in chronic cervical spinal cord injury. The study primarily assessed transplantation safety and examined neurological outcomes such as upper-extremity motor function, sensory function, and hand function.

(2) Evaluation of Functional Improvement

Follow-up imaging did not reveal obvious transplantation-related structural abnormalities. Although trends toward improvement were observed in some motor and hand-function measurements, the overall magnitude of improvement did not meet the prespecified clinical efficacy criteria, and further development of the clinical program was subsequently discontinued.

6.3 CTX0E03

(1) Neural Stem Cell Transplantation for Stroke

CTX0E03 is a conditionally immortalized human neural stem cell line. In the PISCES clinical studies, cells were stereotactically implanted into the brains of patients in the subacute-to-chronic recovery phase after ischemic stroke to evaluate transplantation safety, tolerability, and changes in motor function.

(2) PISCES-2 Study

The PISCES-2 study enrolled 23 patients with ischemic stroke. Some patients showed improvement in upper-extremity motor measurements, although only a limited proportion achieved the prespecified primary endpoint. No clear cell-related serious adverse events were observed during follow-up.

6.4 iPSC-Derived Neural Stem/Progenitor Cells

(1) Transplantation for Subacute Spinal Cord Injury

iPSC-derived neural stem/progenitor cells have entered a first-in-human study in patients with subacute cervical spinal cord injury. Long-term imaging, neurological, and safety follow-up after transplantation has focused on abnormal graft proliferation, tumor formation, and changes in neurological function.

(2) Long-Term Safety and Functional Signals

No graft-related tumor formation was observed in the early small-cohort study, and some patients showed improvements in motor scores and American Spinal Injury Association Impairment Scale (AIS) grades. Because of the small sample size and absence of randomized controls, these functional changes remain preliminary exploratory clinical signals.

7 Products

7.1 Products for Neural Stem Cell Culture, Neural Induction, and Cell Preparation

7.2 Products for Neurotrophic Support and Repair-Microenvironment Research

7.3 Products for Assessing Neural Repair and Transplantation Status

Neural stem cell transplantation contributes to neural injury repair through cell replacement, remyelination, neurotrophic support, and neural circuit reconstruction. Standardization of cell sources, long-term safety, and functional integration between grafts and host neural networks remain central challenges in clinical translation.

References

[1] Fischer I, Dulin JN, Lane MA. Transplanting neural progenitor cells to restore connectivity after spinal cord injury. Nat Rev Neurosci. 2020;21(7):366–383.

[2] Schantz SL, Duberstein KJ, Kaiser EE, et al. Human Neural Stem Cell Therapy for Traumatic Brain Injury—A Systematic Review of Pre-Clinical Studies. J Neurotrauma. 2025;42(7–8):668–688.

[3] Martin JR, Cleary D, Abraham ME, et al. Long-term clinical and safety outcomes from a single-site phase 1 study of neural stem cell transplantation for chronic thoracic spinal cord injury. Cell Rep Med. 2024;5(12):101841.

[4] Levi AD, Anderson KD, Okonkwo DO, et al. Clinical Outcomes from a Multi-Center Study of Human Neural Stem Cell Transplantation in Chronic Cervical Spinal Cord Injury. J Neurotrauma. 2019;36(6):891–902.

[5] Muir KW, Bulters D, Willmot M, et al. Intracerebral implantation of human neural stem cells and motor recovery after stroke: multicentre prospective single-arm study (PISCES-2). J Neurol Neurosurg Psychiatry. 2020;91(4):396–401.

[6] Sugai K, Tsuji O, Fujiyoshi K, et al. An iPSC-derived neural progenitor cell therapy for subacute spinal cord injury: a phase 1 trial with long-term follow-up. Nat Med. 2026.

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